The goals of this project are first, to understand how spinal cord circuits help to coordinate movement in humans and, secondly, to understand how altered functioning of motor circuits contributes to abnormal movement. In FY2005 our clinical studies focused on primary lateral sclerosis, a disorder in which degeneration of the corticospinal tract produces progressive spasticity. This disorder preserves spinal cord neurons, but they do not receive input from the motor cortex. We found that the spinal motor neurons undergo changes in their excitability and firing behavior, such that individual motor neurons tend to fire more slowly, and greater numbers of motor neurons are activated to make stronger movements. These changes are likely to produce less efficient muscle contraction and greater fatigue. We hypothesize that these changes in firing behavior are intrinsic to the motor neuron, and may be caused by changes in behavior of classes of ion channels. A second line of investigation tested whether a subset of PLS patients whose disease progressed in an "ascending" clinical pattern were likely to have degeneration of only the distal ends of the corticospinal axons, i.e. a dying-back degeneration. We hypothesized that movement related cortical potentials, which are generated by shorter axons between cortical motor and pre-motor areas, would be preserved if only the longest corticospinal axons were affected. If movement related cortical potentials were to be spared, these could be used to generate signals for prosthetic devices such as brain computer interfaces. The third study was a pilot investigation to test whether exercise alone can strengthen spinal circuits. Preliminary results in healthy volunteers indicate that circuits that help to produce alternating movements of antagonist muscles can be strengthened by practicing alternating movements.